Ra using inductively coupled plasma–mass spectrometry (ICP-MS) rather than the conventional method of gamma spectroscopy, taking into account an undocumented interference (

F) that is caused by the requirement to use hydrofluoric acid during sample preparation. The unusually high Pb levels observed in a number of soil samples caused significant interferences at the very low concentrations of 

O interference was insignificant under optimized instrument conditions.

As part of a remediation project, soils were analyzed for a list of elements of interest, plus a number of specific isotopes. Inductively coupled plasma–mass spectrometry (ICP-MS) has seen increasing use for the determination of long-lived isotopes in preference to traditional counting techniques because of various efficiencies. In this study, 

Ra were of specific interest. Typically, 

Ra has been determined using gamma spectroscopy. However, determination by gamma spectroscopy requires equilibration of the sample before final determination can be made, and full equilibration can require up to 30 days. Despite this, the initial phases of the remediation work did not allow for such a long delay period, hence ICP-MS was considered as a more rapid evaluation tool. Without this equilibration, there is danger of producing a significant low bias if gamma counting is used, which is a major factor if a reduction in equilibration times is considered. In matters of health and safety, it is always prudent to choose a method with a potential positive bias rather than one with a negative bias. Hence, it was decided that an ICP-MS method should be developed to speed up the determination of 

Ra in soil samples instead of simply reducing the equilibration period before gamma counting. 

It became apparent during the analysis of these samples that they were not typical environmental soils, but more like mine tailings because of the mining and smelter activities over the last several decades in the area they were taken from. Besides having concentrations of many elements that exceeded environmental regulations in Ontario, the lead content in the soils caused an interference on the 

Ra determination by ICP-MS. The known Pb oxide (

Ra was minimized by optimizing instrument conditions so as to have low oxide formation (<3%). The overall impact was therefore found to be insignificant in all of the samples examined.  

However, an undocumented interference was caused by the requirement to use hydrofluoric acid (HF) in the sample preparation to get a complete digestion. The interference caused by 

F, although much greater than that due to oxide formation, is not significant for normal soils. The unusually high Pb levels observed in a number of soil samples caused significant interferences at the very low concentrations of 

Ra being measured. This problem led to the present study. 

Soil samples were dried in ovens at 40 °C for approximately 4–6 h to remove any moisture from the soil without a significant loss of volatiles that were of interest for other measurements. The drying time varied because of the fact that some of the soil samples were extremely wet and contained clay-like material that took a longer time to dry than the other soils. After they were dried, the samples were pulverized and homogenized before being passed through 50 mesh sieves. A representative 0.5-g portion of the dried homogenized samples was digested using a CEM Mars 5 microwave (CEM Corporation, Matthews, North Carolina) using 10 mL of a mixture of ultrapure HNO

, HCl, and HF (8:2:1, respectively). After they were digested and cooled, the samples were quantitatively transferred to clean Environmental Express (Charleston, South Carolina) disposable digestion tubes and bulked to 50 g using >18-MΩ/cm

  water. This represented the "base" working concentration for samples. Appropriate quality control samples were included in the digestion, including acid blanks, sample duplicates, and certified reference materials (contaminated soil SS-2 from SCP Science [Baie D'Urfé, Quebec, Canada], NIST SRM 1645 river sediment, or NIST SRM 1646). 

 Th, As, Sb, Co, Cu, Ni, U, Pb, Ba, Be, B, Cd, Hg, Mo, Se, Ag, V, and Zn using the PerkinElmer (Waltham, Massachusetts) Sciex Elan 6100 DRC ICP-MS system. All samples were diluted a further 10 times from the "base" concentration with >18-MΩ/cm

  water before analysis to minimize both the acid content and the total dissolved solids present in the samples introduced to the ICP-MS. Where possible, multiple isotopes of an element were analyzed to ensure that interferences were not present. The ICP-MS system was calibrated every analytical run using second source standards for quality control standards and internal standardization (with 100 ppb rhodium added using a second channel on the peristaltic pump) to compensate for instrument drift. All standards were matrix-matched to the acid content of the digested and diluted samples.   

Ra using a Varian (Palo Alto, California) 820-MS ICP-MS system. All samples were diluted four times from the "base" concentration with >18-MΩ/cm

  water before analysis to meet the required detection limits for these isotopes. Although this was not an ideal situation, the physical stability of the instrument because of its cone design and 90° reflecting ion optics system (1) allowed for smaller dilution to be used. The ICP-MS system was calibrated every analytical run using second source standards for quality control standards. All standards were matrix-matched to the acid content of the prepared samples. A matrix-matched acid blank was analyzed after every sample to rinse out the system, and the instrument was recalibrated after the analysis of every five samples. 

 Both ICP-MS instruments were optimized daily before sample analysis to ensure that instrument conditions achieved maximum sensitivity, low background, low oxides (<3%), and low doubly charged species (<3%). 

Standards of varying concentrations of lead and HF were prepared to determine the effect of the

Ra. These standards were made using a commercially available single-element lead standard with natural abundance isotope distribution from Inorganic Ventures (Christiansburg, Virginia). The standard was first diluted to produce a 100 ppm intermediate lead standard and finally to the desired working concentrations required for the study. 

The first step was to fix the amount of HF at 1% by weight while varying the concentration of total lead in the standards. The lead standards used were 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, and 20 ppm. The lead standards were made gravimetrically, using the appropriate weight of 100 ppm intermediate standard, adding 1% high-purity HF, and bulking to the appropriate final weight using >18-MΩ/cm

The second step was to fix the amount of lead present at 20 ppm, while varying the concentration of HF in the standard. The concentrations of HF used (all in weight %) were 0.25, 0.5, 1, 2, and 3. Again, the standards were made gravimetrically using the appropriate weight of intermediate Pb standard, adding the appropriate amount of high-purity HF to reach the desired acid concentration, and bulking to the appropriate final weight using >18-MΩ/cm

Pb using the Varian 820-MS ICP-MS system. The system was calibrated before analysis using second source standards for quality control standards. All standards were once again matrix-matched to the acid content of the digested samples that would be analyzed using this method. 

Table sI: Effect of varying concentrations of lead while fixing the concentration of HF at 1% on 226Ra  

The ICP-MS instrument was optimized daily before sample analysis to ensure that instrument conditions achieved maximum sensitivity, low background, low oxides (<3%), and low doubly charged species (<3%). 

Table sI (available online) and Figure 1 show the results of the first step of the study, looking at varying concentrations of lead while fixing the concentration of HF at 1%. As seen in these results, the higher the concentration of Pb, the greater the 

Ra. This effect had been noted when comparing the ICP-MS data to that found by gamma spectroscopy. The second step of the study looked at varying the concentration of HF while keeping the concentration of lead constant. These results are shown in Table sII (available online) and Figure 2. These data show that there is not a direct linear relationship between the concentration of lead and HF in the sample. This is as expected for a moderate equilibrium (equilibrium constant has a moderate value).

Figure 1: Effect of varying concentrations of Pb while fixing the concentrations of HF at 1% on 226Ra.  

Table sII: Effect of varying concentrations of HF while fixing the concentration of Pb at 20 ppm on 226Ra  

Table sIII (available online) and Figure 3 show the 

Ra comparison results between analysis by gamma spectroscopy and ICP-MS (both with and without the correction factor for lead concentration). It is important to note that the gamma data were determined on samples upon arrival at the laboratory, based on 

Ra concentrations are expected to increase during the 30-day in-growth period required for this analysis by gamma spectroscopy. This is clearly seen in samples containing higher concentrations of 

Ra, in which the initial gamma data are significantly lower than those found by ICP-MS using the determined correction factor. However, there is a good correlation between the two techniques when the correction factor is used, as illustrated. 

Figure 2: Effect of varying concentrations of HF while fixing the concentration of Pb at 20 ppm on 226Ra.  

Because a constant concentration of HF is generally used for sample digestion in a given study, a simple correction factor can be experimentally determined for any given level of HF rather than using a more complex correction equation. A complex correction equation also could be determined by a more extensive study of the Pb–F equilibrium under spectroscopic conditions. This factor was determined for the HF concentration that was used for the digestion of the soils for this remediation work: The more tightly experimental conditions are controlled (particularly the acid digestion), the more accurate the results of the correction factor. ICP-MS was the method of choice for the determination of 

Ra because of the required turnaround times for this project (24–48 h from date of receipt at the laboratory). As mentioned above, 

Ra determination by gamma spectroscopy requires an equilibration time of up to 30 days for the sample before final determination to avoid significant low bias. An extended commentary on radiochemical methods is required to explain why no viable alternatives existed using the gamma measurement method. In matters of health and safety, it is always prudent to choose a method with a potential positive bias rather than one with a negative bias. Therefore, to meet the required timelines, ICP-MS was used for

To further test the accuracy of the data produced using the ICP-MS method for the determination of 

Ra, the Kinectrics Inc. laboratory (Toronto, Ontario, Canada) participated in an interlaboratory study from Environmental Research Associates (ERA) in Arvada, Colorado (Study RAD-84). The value determined by the laboratory was 7.81 pCi/L 

Ra. The preliminary assigned value was reported as 8.26 pCi/L 

Ra; therefore the value determined using this method was well within the preliminary acceptance limits of 6.21–9.71 pCi/L 

Ra in soil samples in the presence of high concentrations of Pb was not a straightforward analysis. However, a correction factor was determined that could be applied to the 

Ra data to account for this interference. This correction factor worked well, as seen when 

Ra found by gamma spectroscopy was compared to the ICP-MS data, showing a very good correlation between the two independent techniques. Any additional method improvements would require chemical separations for sample cleanup before analysis or the use of a sector-field ICP-MS system to improve the distinction between species (hence smaller correction factor). 

 are with Kinectrics Inc., Toronto, Ontario, Canada. Direct correspondence to: 

(1)  Varian 810-MS and 820-MS ICP Mass Spectrometers Specification Sheet, SI-0184 10/05. 

(2) Environmental Research Associates Study RAD-84, February 2011. 

Articles

Article

This article describes a way to measure 226Ra using inductively coupled plasma–mass spectrometry (ICP-MS) rather than the conventional method of gamma spectroscopy, taking into account an undocumented interference (207Pb19F) that is caused by the requirement to use hydrofluoric acid during sample preparation. The unusually high Pb levels observed in a number of soil samples caused significant interferences at the very low concentrations of 226Ra that were measured. The expected 208Pb18O interference was insignificant under optimized instrument conditions.

The Determination of 226Ra in Nontypical Soil Samples by ICP-MS

The direct analysis of seawater by inductively coupled plasma–mass spectrometry (ICP-MS) is notoriously difficult because of the high matrix content of the sample that leads to both spectroscopic (for example, polyatomic interferences) and nonspectroscopic interferences (for example, signal suppression). Additionally, the low target concentration levels demand a noncontaminating, robust sample introduction technique. The latest ICP-MS techniques provide high-throughput methods that are able to process large numbers of samples presented for analysis.

The oceans cover 71% of the planet and have a combined volume of 1.4 × 10

  cubic miles). Any attempt to understand the chemical inputs to the planet's ecology must include a close look at seawater. Toxic substances and high concentrations of certain trace elements may present a health hazard for irrigation, swimming, fishing, boating, and industrial uses. These conditions also can affect wildlife, which use the water for drinking or a habitat.  

The analysis of trace elements in seawater is one of the most challenging analytical tasks in the field of environmental monitoring, mainly because of matrix interferences from its high dissolved salt content. In recent years, methods of adequate sensitivity became available for true ultratrace-metal determinations in drinking water. However, in the case of seawater, only now has it become possible to both resolve the complex mixtures and achieve the very low detection limits required.  

The most commonly employed method of analysis for trace metals in seawater is inductively coupled plasma–mass spectrometry (ICP-MS). Although the technique is very powerful by virtue of its sensitivity and selectivity, it is limited in terms of the amount of dissolved solids that can be introduced. When aspirating samples with high levels of dissolved solids, salt may deposit on the interface (cones) during the analytical run, degrading signal stability. Additionally, high levels of dissolved salts can cause spectral (polyatomic) interferences. Because these interferences originate from the seawater matrix itself, standard ICP-MS for seawater analysis can often lead to false positive results that are much higher than the actual concentrations in the solution.  

To address these analytical challenges, a range of different sample preparation and introduction techniques have been coupled with ICP-MS. This article demonstrates the contamination-free, fully automated, direct, trace-metal analysis of seawater using a specialized sample introduction system in conjunction with ICP-MS. 

The results in this study were obtained using an Elemental Scientific Inc. (Omaha, Nebraska) PC3 Fast sample introduction system with a Thermo Scientific (Bremen, Germany) XSERIES 2 ICP-MS system.  The ICP-MS system was configured with the sample introduction system in combination with an autosampler. The schematic in Figure 1 outlines the principle of the sample introduction system, which utilizes a vacuum pump to load samples onto a PFA loop mounted across a six-port switching valve. In addition to providing direct, routine trace-metal analysis of high matrix samples including seawater, the system ensures high sample throughput and minimizes sample deposition on the ICP-MS interface for increased long-term stability. The system also ensures minimal contamination as a result of automated sample manipulation and short sample pathway consisting of high-purity components.  

Figure 1: Schematic of the sample introduction system.  

The ICP-MS instrument parameters are outlined below. 

Spray chamber: Quartz cyclonic spray chamber 

Injector: Demountable torch with a 2.5-mm diameter 

Additional gas: 2% methane in argon at 100 mL/min 

Collision cell: 4.0 mL/min 7% hydrogen in helium at 2 V (kinetic energy discrimination [KED] mode) 

As part of the experiment, undiluted seawater samples were loaded onto the autosampler and the internal standard containing diluent was added online using a T-piece located directly after the exit port from the Fast valve before the nebulizer. The ratio of seawater to diluent was 1:7. Online dilution is recommended to minimize unnecessary contamination. The NASS-5 and CASS-4 seawater reference material standards for trace metals (National Research Council Canada, Ottawa, Ontario) were selected to evaluate accuracy. Locally sourced filtered and acidified seawater was spiked to 10 ppb with a range of elements and used for the long term stability evaluation. A three-point external calibration was used for quantification with standard concentrations chosen relative to the expected concentration in the samples. Gallium (Ga), yttrium (Y), indium (In), and bismuth (Bi) were used as internal standards. All elements were measured in KED mode using the standard single gas mixture of 7% hydrogen (H

) in helium (He) for optimum sensitivity and interference suppression. 

Figure 2 shows the external calibration curves for the determination of trace metals in seawater by ICP-MS; the selection of elements includes iron, nickel, copper, and zinc. Figure 3 compares the raw count rates for the internal standards in both a 2% nitric acid (HNO

) and an undiluted seawater sample measured. Signal suppression of <20% was found in the undiluted seawater. 

Figure 2: Calibration curves for Fe, Ni, Cu and Zn. 

Figure 3: Internal standard count rates (counts per second) from Thermo Scientific PlasmaLab software. Suppression in the 1:7 diluted seawater is less than 20%.  

Quantitative results for the seawater samples measured are shown in Table I. The findings indicate a good agreement between measured and certified values. To assess the stability of the analysis method, 180 samples of 10 ppb spiked seawater were analyzed using the described system over a 6-h period. The stability of the recovery for the 10 ppb spike is shown in Figure 4. 

Table I: Comparison of measured with certified values for the NASS-5 and CASS-4 reference materials. Detection limits (ng/mL) were calculated from 3 standard deviations of 100 blank runs. 

Figure 4: Measured values in 10 ppb spiked Bremerhaven seawater for 180 samples over a6-h period.  

To understand the quality of seawater, the analysis of its chemical properties is vital. The ability to effectively undertake such analyses is invaluable for seawater environmental protection. 

The method described in this work provides a rapid, contamination free sampling technology with full automation for high sample throughput. Through implementation of the new method, previous limitations on total dissolved solids with ICP-MS are eliminated, providing a sensitive and interference-free instrumental solution for trace-elemental determination even in difficult matrices such as seawater. 

 is an ICP-MS application specialist at Thermo Fisher Scientific in Bremen, Germany. 

http://www.epa.gov/regulations/laws/cwa.html

Overcoming the Challenges Associated with the Direct Analysis of Trace Metals in Seawater Using ICP-MS

 General Chapter <231> "heavy metals limit test" will be replaced by new instrumental methods, 

<232> (Limits) and <233> (Procedures), in 2013. 

The presence of impurities in pharmaceutical samples is a concern, not only because of potential toxicity, but also because of the potential impact on drug stability, shelf-life, or unwanted side-effects. As a result, both organic and inorganic (elemental) impurities must be monitored and controlled in raw materials used for drug manufacturing, in intermediates and active pharmaceutical ingredients (APIs), in excipients (stabilizers, fillers, binders, colorings, flavors, coatings, and so forth), and in final drug products. Impurities that may be added during the production process, such as catalysts and contaminants from production process equipment, must also be monitored.   

The current method used for monitoring inorganic contaminants in pharmaceutical samples is a 100-year-old colorimetric test, defined in 

 General Chapter <231>. This method, known as the "heavy metal limit test," is not specific for individual analytes, and does not include many elements of interest, such as Cr and the catalyst metals. 

 <231> is that the sample preparation method requires ignition of the sample at temperatures up to 600 °C, which leads to loss of volatile analytes, including the critical toxic element Hg (1–4). 

USP is currently developing two new General Chapters 

 <232> (Limits) and <233> (Procedures), which will be implemented in 2013. The new methods will address the limitations of the current method, especially the list of analytes and the use of closed-vessel sample digestion and modern instrumental techniques for the accurate recovery and determination of individual analyte concentrations. 

Table sI (available online) shows the permitted daily exposure (PDE) limits for the new list of 16 analytes (As, Cd, Hg, Pb, V, Cr, Ni, Mo, Mn, Cu, Pt, Pd, Ru, Rh, Os, and Ir) defined in 

 <232> (5). This analyte list was developed based on toxicological data, rather than method capability, and for the first time the list includes catalyst elements (the platinum group elements [PGEs] Pt, Pd, Ru, Rh, Os, and Ir). 

 <232> also contains a section relating to the elemental form (species) of elements, and notes that As and Hg are of particular concern as some forms are much more toxic than others.  

Table sI: USP  permitted daily exposure (PDE) limits for drug products and concentration limits for components (drug substances and excipients) of drug products with a maximum daily dose â¤10 g/day (5), together with ICP-MS system detection limits.  

Although the required PDE limits defined in 

 <232> can be easily measured with either of the instrumental techniques referenced in 

 <233> (inductively coupled plasma–mass spectrometry [ICP-MS] or inductively coupled plasma–optical emission spectrometry [ICP-OES]) (6), many novel drugs may only be available in very small amounts. The large dilution associated with the preparation of these mg-scale sample weights means that instrumentation with the lowest possible detection limits may be essential. 

 <232> also provides individual component limits for drug substances and excipients, assuming a maximum daily dose not more than 10 g/day. These component limits are applicable to manufacturing quality control as they allow drug manufacturers to control the concentration of impurities in the raw materials and intermediates used in the final drug product. For any sample requiring digestion or dilution, the PDE limits must be corrected for the dilution factor applied during sample preparation. For example, the individual component limit for Cd is 0.5 µg/g (ppm) for solid drug products and excipients. A dilution factor of 250× during sample digestion would give a PDE limit in the sample digest (the "J" value) of 2 ng/mL (ppb) for Cd. Accurate recovery must be demonstrated at 0.5J (1 ng/mL), suggesting a required detection limit at least 10× lower than this (0.1 ng/mL) a concentration easily measured using ICP-MS, as shown in Table sI. 

The limits shown in Table sI are based on oral administration and also are modified depending on the route of administration. Component limits for drug products and excipients that would be delivered by parenteral or inhalational administration must be 10× lower than these values, suggesting a required detection limit of 0.01 ng/mL, still easily within the range of ICP-MS. 

A wide range of possible samples may be analyzed using 

 <232> and <233>. Some pharmaceutical samples can be analyzed directly (unsolvated), while others can be prepared using simple dilution or solubilization in an aqueous solvent (such as water or dilute acid) or a suitable organic solvent (such as 25:75 2-butoxyethanol–water [3], DMSO, or DGME). For many APIs, dilution in an organic solvent is the preferred approach, in which case it may be necessary to include some means of stabilizing the analytes to avoid variable recovery due to the presence of more or less volatile species compared to the calibration standard (7). 

 <233> defines the sample preparation and method validation procedures that should be used for system suitability qualifications to ensure that the analysis is "specific, accurate, and precise" (6). 

 In practice, most laboratories are likely to opt for one of the ICP techniques, due to their ability to handle a wide range of sample types and to measure all required elements in a single rapid analysis (8,9). 

 In this study, we performed method validation and system suitability performance testing of ICP-MS for the analysis of pharmaceutical products, according to the May 2011 revision of 

Many raw materials, excipients, intermediates, APIs, and final products will be insoluble in aqueous or organic solvents, and will therefore require acid digestion. 

 <233> specifies the use of "strong acids" for digestion and there are some general points that will apply to most sample types that require digestion:  

 <232> includes Hg and the PGEs. These elements are chemically unstable in an oxidizing matrix, such as nitric acid (HNO

) (10,11), and can only be stabilized and measured reliably over an extended period if the digest solution includes a complexing agent such as HCl. We prepared all samples using a digestion matrix of 1% HNO

 and 0.5% HCl to ensure stability of Hg and the PGEs.

Pharmaceutical products may be a complex combination of the API, plus fillers, binders, colorings, and coatings. These coatings may be organic polymers that are formulated to resist acid attack in the stomach and thereby control the point at which the drug substance is released in the small intestine. Closed-vessel (high temperature and pressure) microwave digestion is the preferred digestion technique referred to in 

<233> for solid samples. Closed-vessel digestion also eliminates any issues of loss of volatile elements such as Hg, which is a problem with

All 16 elements specified in the May 2011 revision of 

 <232> were measured using ICP-MS. The full suite of analytes plus internal standards was measured in calibration standards, multiple replicates of digested gelatin capsule (gelcap) samples, and samples spiked at the levels specified in 

 <233>. The ICP-MS system provided a high plasma temperature (low CeO/Ce ratio of around 1%), which delivered good matrix decomposition and high sensitivity for poorly ionized elements such as As, Cd, Hg, and the PGEs: Os, Ir, and Pt. The system also includes a Peltier-cooled spray chamber, which is preferred in 

The ICP-MS system was operated in helium (He) collision mode, which eliminates matrix-based polyatomic interferences regardless of sample composition and without the sample-specific or analyte-specific optimization that is a characteristic of reaction cell methods (12). He mode operation allows samples that contain high and variable amounts of chloride to be run without compromising the detection of elements that can suffer from chloride-based polyatomic overlaps.  These elements include 

Cl). The operating conditions used for the analysis of gelcap sample digests are shown in Table II. 

Table II: ICP-MS system operating conditions  

An additional benefit of He mode operation is that it removes the polyatomic interferences from all isotopes of each analyte, so secondary or qualifier isotopes are available for analyte confirmation. 

 <233> specifies that the procedure must be able to unequivocally assess each target element in the presence of other sample components such as other analytes and matrix components. The use of secondary isotopes as qualifier ions for ICP-MS is a well-established and unique capability of He mode (13). 

A standard 7700x ICP-MS system from Agilent Technologies (Santa Clara, California) was used throughout. The collision–reaction cell (CRC) ICP-MS uses an octopole reaction system (ORS

 ) for removal of polyatomic interferences. The ORS was operated in He mode for all analytes and all samples, demonstrating the simple method setup and routine operation provided by ICP-MS. Primary and secondary (qualifier) isotopes, cell mode, integration times, and method detection limits (MDLs) for all analytes are shown in Table sIII (available online). The MDLs were calculated from threefold the standard deviation of 10 external measurements of unspiked gelcap samples. 

Table sIII: Acquisition modes and analytical figures of merit  

External calibrations were prepared from single-element ICP-MS stock solutions at 1000 ppm. Because several of the target elements are not stable unless HCl is present in the solution, the intermediate stock solution was prepared in the same acid mix used for the final sample dilutions (1% HNO

 and 0.5% HCl). Example calibration plots of the four most critical elements As, Cd, Hg, and Pb are shown in Figure s1 (available online). Good linearity and sensitivity were demonstrated for all elements, and the low background equivalent concentration (BEC) for As demonstrated the effective removal of the ArCl polyatomic interference. 

Figure s1: Calibrations for As, Cd, Hg, and Pb demonstrating excellent linearity and low backgrounds.  

System Suitability Check and Method Validation

 <233> requires that a standardization solution at 2J (two times the control limit corrected for sample dilution) is measured before and after the sample batch. The drift between these two solutions must not exceed 20%. 

To confirm the long-term stability of the results we used the 2J standard as a continuing calibration verification (CCV) quality control (QC) check run periodically during the 7 h sequence. The results for the sequence are summarized in Table sIV (available online), demonstrating that the initial calibration remained valid with overall drift from the first to last CCV of less than 7.5% for all elements and less than 2% for many. This demonstrates the robustness of ICP-MS for the routine analysis of pharmaceutical samples. 

Table sIV: Stability and drift for gel cap samples spiked at 2J  

 <233> depend on the procedure used and whether it is a limit procedure or a quantitative procedure. 

 must confirm detectability, repeatability, and specificity of the measurement, and 

 must demonstrate accuracy, precision (repeatability and ruggedness), and specificity.  

Limit procedures must be capable of detecting a sample spike by comparing the measured result for a sample spiked at 1J, against a standard solution prepared at 1J. The spiked sample mean result must be the same as (within ±10%) or greater than the value obtained in the standard solution. The procedure must also be able to distinguish between a test sample spiked at the target concentration (1J) and a sample of the same material spiked at 80% of the target concentration (0.8J). The result for the sample spiked at 0.8J must be less than the result for the sample spiked at 1J. Repeatability must be demonstrated by meeting an external precision limit of no more than 20% RSD for six separate samples spiked at the spike levels. 

Results for the limit procedure validation of gelcaps measured using ICP-MS are shown in Table V. The mean results for six external repeats of the standard at 1J, six gelcap samples spiked at 1J, and six gelcap samples spiked at 0.8J are presented. The results confirm excellent accuracy and repeatability, easily within the validation requirements for both spike recovery and discrimination. Specificity is also demonstrated through the use of secondary isotopes to confirm unequivocal assessment of each target element in the presence of other analytes and the matrix components. 

Table V:  Accuracy of spike recovery at 1J in gel caps, and discrimination between spikes at 1J and 0.8J (n = 6 for each sample)  

Quant procedures must demonstrate accurate spike recovery (between 70% and 150% of the spike value) for the mean of three samples spiked at concentrations ranging from 50% to 150% of the J value (0.5J to 1.5J) for each target element. In this validation, we used spikes at 0.5J and 1.5J, as well as the 0.8J and 1J spikes measured for the limit procedure. Six separate (external) samples were analyzed for each spike level. 

Repeatability must be demonstrated by an external precision not more than 20% RSD for six separate samples spiked at the indicated levels. Ruggedness must also be assessed and cannot be more than 20% RSD when the repeatability test is repeated on different days, on different instruments, or by different analysts. As with limit procedures, specificity must be demonstrated through unequivocal assessment of each target element (confirmation of the result using a secondary isotope). 

The data in Table sVI (available online) show the summary results for the ICP-MS quant analysis of gelcaps, with six replicates for each spike level. The only data item not presented is the repeated analysis to demonstrate the ruggedness of the method, but a second analysis on a different day gave results well within the ruggedness criteria of no more than 20% RSD. Spike recoveries were all well within the required limits (70–150%) and repeatability was in the low % level, easily meeting the required acceptance criteria of no more than 20% RSD. 

Table sVI: Accurate spike recovery and precision at 0.5J and 1.5J in gel cap samples (n = 6 for each sample)  

 <232> and <233> methodology for the preparation and analysis of pharmaceutical samples provides an opportunity for pharmaceutical laboratories to update their methodology and instrumentation and address the limitations of the current "heavy metals limit test" (

 <231>). With closed-vessel microwave digestion and element stabilization using HCl, ICP-MS has proven to be capable of routine determination of all regulated elements at low levels in pharmaceutical samples. 

All regulated elements passed the acceptance criteria defined in 

 <233> for both Limit and Quantitative procedures, including those elements that can suffer matrix-based interferences (such as the ArCl overlap on As), and those that are more soluble or stable in chloride matrix, particularly Hg which can be stabilized using a low percentage level of HCl. Routine addition of HCl to stabilize samples is no longer a problem for ICP-MS methods, because the resulting Cl-based polyatomic interferences are reliably removed using He cell gas mode on CRC-based ICP-MS instruments. 

System performance validation data was easily within the method requirements for accuracy, precision, and spike recovery, and detection limits were all several orders of magnitude lower than the levels at which the trace elements are controlled. 

Unequivocal identification and quantification of target elements is provided using secondary or qualifier isotopes for confirmation of the result reported at the primary isotope. ICP-MS also can be linked to a chromatography system to provide integrated separation and analysis of the different forms or species of As and Hg, as required under 

 is with Exova USA in Santa Fe Springs, California. 

The current United States Pharmacopeia (USP) General Chapter <231> "heavy metals limit test" will be replaced by new instrumental methods, USP <232> (Limits) and <233> (Procedures), in 2013.

Validating ICP-MS for the Analysis of Elemental Impurities According to Draft USP General Chapters <232> and <233>

This study focuses on the use of inductively coupled plasma–mass spectrometry (ICP-MS) in Chinese laboratories for measuring toxic, essential, and nutritional elements in foods. In particular, we describe recent advances in detection systems and interference removal capabilities to provide fast and simple multielement analysis over a wide concentration range for many different types of food samples. 

Globalization of the food industry has opened up new markets to many countries, resulting in greater scrutiny by regulatory agencies and driving the need for increased food testing and safety. China, in particular, is a major provider of food products on a global scale, ranking in the top five nations for food-related exports. Unfortunately, a number of food scares, including melamine contamination in pet foods and infant formula, has placed China in the headlines for all of the wrong reasons. China is a key supplier of fruits, vegetables, rice, nuts, beans, and products derived from them, including juices, preserves, pastes, and purees. For example, according to Food and Agriculture Organization of the United Nations (FAOSTAT), China was by far the biggest exporter of nonconcentrated apple juice and the third largest exporter of tea in 2008, exporting more than $1.1 billion and $0.7 billion, respectively (1). 

The Chinese government is committed to protecting consumers and customers. This is illustrated by the annual China International Food Safety & Quality (CIFSQ) conference and exposition, which will be held in Beijing this November (2). Now in its fifth year, this conference brings together regulators and industry stakeholders from around the world, giving them the opportunity to meet, collaborate, and provide solutions to strengthen global food safety. The demand for improvements in food quality also has seen a rise in the demand for analytical instrumentation over the past decade as laboratories strive to meet ever-more stringent food quality regulations. Techniques such as gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–mass spectrometry (LC–MS) for detecting and quantifying pesticide levels; nuclear magnetic resonance (NMR) for product classification and ingredient identification of juices; and inductively coupled plasma–mass spectrometry (ICP-MS) for carrying out the multielement determinations of macro and trace minerals in foodstuffs, are all powerful analytical tools commonly used in Chinese food testing laboratories. 

Foods and agricultural crops contain various concentrations of nutrients, which can range from trace amounts to percentage levels. However, while most of their nutritional content is intended for maintaining good health, the benefits of the desired mineral content can be compromised by concentrations of elements considered to be toxic to humans or animals. The health effects of dietary exposure to different levels of minerals and metals have been widely investigated, and based on the concentrations at which deficiencies and toxicities are observed, inorganic elements may be divided into four main groups:   

: A regular intake of large quantities of elements such as Ca, Mg, Na, K, P, S, Fe, Cu, and Zn is needed to sustain life. 

: A smaller quantity of each of these elements ensures good health. Examples include Mn, Cr, Se, B, Br, Si, I, V, Li, Mo, Co, Ge, and others.

: Some studies propose the human body's requirement for other elements like F, As, Rb, Sn, Nb, Sr, Au, Ag, Cr, and Ni.

: Dietary intake of deleterious elements such as Be, Hg, Pb, Cd, Al, Sb, Bi, Ba, and U should be minimized. 

Greater exposure to toxic metals in the modern diet has been suggested as a contributing factor to the increase in diseases such as diabetes, hypothyroidism, and cancer. Similarly, looking upstream in our food supply chains and in particular to the agricultural industry, it is becoming increasingly clear that providing the correct balance of macrominerals and trace metals in the feed of livestock helps them thrive and remain disease-free. For example, magnesium intake is critical to prevent grass tetany, a fatal metabolic disorder in cattle. Selenium is known to be a major factor in the fertility of cows, and cobalt supplements are often necessary for the well-being of sheep. Accurate measurement of elemental composition in food and agricultural products is therefore essential to ensure product safety and maintain adequate levels of nutritional content. 

ICP-MS is particularly ideal for characterizing the elemental composition of food materials because it provides a fast and relatively simple multielement characterization over a wide concentration range for many different sample types. With recent advances in technology, including detection systems and interference removal techniques, the toxic elements that are often present at ultratrace levels can now be measured accurately at the same time as essential and nutritional minerals, which are often present at high parts-per-million levels or low percentage levels. As a result, ICP-MS is now routinely used in Chinese laboratories for measuring the full suite of elements in foods. Before we take a look at what is driving these applications, let's remind ourselves why ICP-MS is ideally suited for the analysis of foodstuffs, compared to other trace element techniques, such as inductively coupled plasma–optical emission spectrometry (ICP-OES), flame atomic absorption (FAA), and electrothermal atomization (ETA).  

ICP-MS typically offers very high sensitivity and extremely low detection limits, especially for heavy metals. For example, the detection limit for Pb is approximately 2–3 orders of magnitude lower than ETA, 4 orders of magnitude lower than ICP-OES, and more than 5 orders of magnitude lower than FAA (3).

The technique is a rapid multielement technique covering 8–9 orders of linear dynamic range, meaning parts-per-trillion (ppt) levels can be determined in the same sample as high parts-per-million concentrations. By comparison, ICP-OES offers 5–6 orders, FAA offers 3–4 orders, and ETA offers only 2–3 orders of linearity. 

High and low analyte concentrations can be determined in the same sample run using a pulse-only detection system. This capability eliminates the need for analog measurements, which allows the dynamic range to be extended without having to carry out regular and time consuming cross-calibration of the detector in a multielement analysis (4).

Isotopic measurements are unique to ICP-MS compared to the other atomic spectroscopic techniques. This means that analyses such as nutritional isotope ratio tracer studies can be carried out to study the adsorption of certain minerals into the bloodstream. Traditionally, this has been the domain of multicollector magnetic sector instruments, but with the recent development of all-digital (pulse-only) detectors, excellent precision can be obtained for isotope ratios covering concentrations over the full dynamic range (5).

Spectral interferences created by the sample matrix and plasma gas have traditionally been a problem in ICP-MS. However, with the development of collision and reaction cells and interfaces about 10 years ago, the technique is now capable of determining elements such as As, Se, Cr, V, and Fe at the parts-per-trillion level in the presence of problematic sample matrices that generate polyatomic species derived from Ar, O, H, Cl, and C ions (6).

National Food Safety Standard (NFSS) Maximum Levels of Contaminants in Food

On August 12, 2010, China's Ministry of Health, under the guidance of the Chinese Center for Disease Control Nutrition and Food Safety (CCDCNFS), notified the World Trade Organization (WTO) that it was replacing GB 2762-2005, the National Standard for the Maximum Levels of Contaminants in Foods,

with a new standard to address the maximum levels of lead, cadmium, mercury, arsenic, tin, nickel, chromium, nitrate, nitrite, benzo[

-nitrosamines, polychlorinated biphenyls, and 3-chloro-1,2-propanediol in foodstuffs (7). This standard, which is yet to be given a numerical identification, will replace the previous standard, GB 2762-2005 (8). The major modifications being proposed in the new standard are as follows:  

Maximum contaminant levels for some of the of existing foods have been adjusted, together with the inclusion of a number of additional foodstuffs to reflect 

 (CAC) standards, a joint publication of the Food and Agricultural Organization (FAO) of the United Nations and the World Health Organization (WHO) (9).

The new standard includes a definition for "edible parts" of the food and prescribe that the maximum levels only apply to the edible or drinkable parts of the food raw materials after the nonedible parts are removed by mechanical means.

Elimination of selenium, aluminum, fluorine, and the rare earth elements from the standard. 

Addition of tin, 3-chloro-1,2-propanediol, and nitrate to the standard.

-nitrosamine standard will be defined as 

-nitrosodimethylamine and not a combination of 

This new standard is clearly China's attempt to improve its image with the international community. For example, the number of food products listed for lead (Pb) has increased from 17 in 2005 to 58 in the new standard. Some of the food products that have been added include bottled water, carbonated beverages, chocolate products, jams and preserves, and bakery items, which is a reflection of China's status as a leading exporter in today's global economy. Many of the other analytes specified in the standard also have additional food materials listed. 

Now let's take a brief look at some typical applications researchers are carrying out with ICP-MS to support this new Chinese standard. The study is not meant to be comprehensive, but rather an overview of what is being done by Chinese laboratories and the capability of cutting-edge technology like ICP-MS to address their analytical needs. The three applications highlighted will be  

Determination of Pb, which in tea demonstrates the ability of the technique to measure single-digit milligram-per-kilogram (parts-per-million) levels of lead in dried tea leaves. This work was carried out by researchers at the Ministry of Agriculture's Food Quality Supervision and Testing Center in Shanghai. The sample data are the researchers' own quality control (QC) standards and samples and are not yet published.

Determination of Cd in rice, which demonstrates the ability of ICP-MS to measure even lower microgram-per-gram (parts-per-billion) levels of cadmium in rice flour. This work was also carried out by researchers at the Ministry of Agriculture's Food Quality Supervision and Testing Center in Shanghai. The sample data are the researchers' own QC standards and samples and are not yet in the public domain.

Determination of Ca, Mg, K, Pb, Cd, Hg, As, Sn, Ni, and Cr in apple leaves. This work highlights the capability of ICP-MS to determine elements at high (%) levels together with elements at trace (microgram-per-gram) levels in the same multielement analysis of a NIST certified reference material. This work was carried out at our own application laboratory and is currently unpublished.

Even though the work was done in two laboratories, all samples were brought into solution with a MARS 5 (CEM Corporation, Matthews, North Carolina) microwave digestion system using a similar sample preparation methodology, described below. 

A 0.2–0.5 g sample was weighed into a digestion vessel. Then, 7 mL of 70% nitric acid was added, the pressure cap was tightened, and the vessel was inserted into the microwave oven, which used the temperature-control mode shown in Table sI (available online). After digestion, the solutions were made up with 18-MΩ ultrapure water to a volume of 50 mL or 100 mL, depending on the sample type. 

Table sI: Microwave digestion protocol for the analysis of foodstuffs by ICP-MS  

After they were in solution, the analytes were determined by ICP-MS with a Bruker (Fremont, California) Aurora M90 system using the instrument conditions and calibration standards shown in Table sII (available online). This system has been described in the open literature, but it is basically a high sensitivity instrument that uses a 90° ion mirror and off-axis quadrupole. Additionally, it uses a collision reaction interface (CRI) where collisional and reactive gases are bled into the skimmer cone to minimize the formation of problematic polyatomic ions. The instrument also offers the capability to extend the linear dynamic range using a pulse-only detection system to determine percentage levels at the same time as measuring trace and ultratrace analyte concentrations (10). 

Table sII: ICP-MS instrumental conditions for the analysis of dried tea, rice flour, and apple leaves  

There are a number of points that should be emphasized:   

Even though this study only reported nine elements specified in the new National Food Safety Standard, 18 elements were determined in the NIST 1515 CRM apple leaves. 

For the analysis of apple leaves, the lens voltages were automatically adjusted to maximize the ion signal for the nine elements being determined. For the analysis of the tea leaves and rice flour, the ion lens voltage optimization was weighted toward Pb and Cd. 

No CRI gas was used for the determination of Pb or Cd, because these analytes are basically free of spectral interferences in these matrices. For the multielement analysis of apple leaves, a mixture of hydrogen and helium gas was bled into the skimmer cone interface to minimize the impact of polyatomic interferences such as Ar

No signal attenuation was required for the determination of Pb or Cd because the analyte concentrations were extremely low. However, for the analysis of the apple leaves, Ca, Mg, and K were present at low percentage levels, which made it necessary to extend the dynamic range with the automated pulse-only, digital detector to allow the determination of the other low parts-per-million analytes at the same time.

The results for the analysis of a quality control standard plus an actual unknown tea leaf and rice flour sample are shown in Table I, and the multielement analysis of NIST 1515 CRM apples leaves, including statistical data, is shown in Table II. 

Table I: Results for the determination of Pb in tea leaves and Cd in powdered rice  

China's image as a global supplier and exporter of foodstuffs has been severely tarnished over the past few years by various food safety and contamination scares. The new National Food Safety Standard is clearly China's attempt to improve its standing with the international community. Only time will tell whether this regulatory mandate by the Chinese Ministry of Health will bring Chinese food producers into line with the stricter quality protocols of manufacturers in the United States and Europe. 

Table II: Results for the determination of Ca, Mg, K, As, Pb, Hg, Ni, Cr, and Cd in NIST 1515 CRM apple leaves  

This study also has shown that ICP-MS will play a very important role in this effort. There is no question that to meet many of the new levels and additional foodstuffs prescribed in the standard, existing elemental techniques like AA and ICP-OES are just not going to be able to meet the detection limits, multielement capability, and sample throughput demands of modern food laboratories. There is no question that by investing in other cutting-edge analytical tools like LC–MS, GC–MS, and NMR, in addition to ICP-MS, Chinese researchers are showing the world that they are capable of meeting this demand. 

This brief study shows that recent innovations in ICP-MS have enabled researchers to determine extremely low concentrations of elements like Pb and Cd at microgram-per-kilogram (parts-per-billion) levels in the solid material. In addition, when required, the technique has the ability to accurately measure macrominerals such as Ca, Mg, and K that are present at low percentage levels, together with essential trace metals like Cr and Ni, and ultratrace levels of toxic metals like Cd and Hg in the same multielement method. 

This study focuses on the use of inductively coupled plasma–mass spectrometry (ICP-MS) in Chinese laboratories for measuring toxic, essential, and nutritional elements in foods. In particular, we describe recent advances in detection systems and interference removal capabilities to provide fast and simple multielement analysis over a wide concentration range for many different types of food samples.

Special Issues-11-01-2011

The Determination of 226Ra in Nontypical Soil Samples by ICP-MS

Overcoming the Challenges Associated with the Direct Analysis of Trace Metals in Seawater Using ICP-MS

Validating ICP-MS for the Analysis of Elemental Impurities According to Draft USP General Chapters <232> and <233>

Ensuring the Safety and Quality of Foodstuffs Produced in China: The Role of ICP-MS